Genetic Landscape of Mucosal Melanoma: Identifying Pathogenic Germline Variants

Abstract

Mucosal melanomas (MM) are rare but aggressive malignancies, comprising only 1.3% of all melanoma diagnoses, with a poor 5-year survival rate below 20%. MM lacks identifiable risk factors, presents with distinct mutational profiles, and is often diagnosed at an advanced stage, contributing to worse outcomes. This study explores the prevalence of pathogenic germline variants associated with melanoma and general cancer susceptibility in a cohort of 16 MM patients enrolled in the Gross Family Melanoma Registry at Cleveland Clinic between 2017 and 2023. Germline testing was performed using an ≥ 81 gene panel, including 12 genes with established or preliminary melanoma predisposition evidence. Our findings reveal a high prevalence (50%) of pathogenic germline variants among MM patients, with CHEK2 and APC variants identified in 12.5% of cases each, and individual variants detected in MUTYH, ATM, RB1, and RECQL4. These results suggest a germline-driven cancer susceptibility in MM, exceeding the 15% prevalence observed in cutaneous melanoma using the same inclusion criteria.

Keywords: cancer susceptibility; genetic predisposition to disease; genetic testing; genetics; melanoma; mucosal melanoma.